Drugs in Context

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Authors: Rechelle Tull MD, William D Hoover III MD, Jacqueline F De Luca MD, William W Huang MD, MPH, Joseph L Jorizzo MD

Eosinophilic fasciitis is an uncommon connective tissue disorder that affects patients of all ages, resulting in significant morbidity. Systemic corticosteroids can induce remission of disease. However, there is no universally accepted treatment ladder for eosinophilic fasciitis. This case series evaluates treatment efficacy in patients with eosinophilic fasciitis seen at Wake Forest University Department of Dermatology outpatient clinics. Patient charts were screened using ICD-9 diagnosis code 710.9 (unspecified diffuse connective tissue disease) to identify patients with eosinophilic fasciitis (n=10) seen at our institution. Patients were treated for an average 24 months with a combination of methotrexate and prednisone therapy, unless one or both were contraindicated, with each medication tapered conservatively to prevent disease flares. Alternate treatments included mycophenolate mofetil with prednisone, azathioprine with prednisone, prednisone monotherapy, and methotrexate monotherapy. Disease remission off therapy and on low-dose therapy was 66 and 70%, respectively. Our first-line therapy of concomitant methotrexate and prednisone is well-tolerated and effective for managing patients with eosinophilic fasciitis. Our study was limited to cases seen at a single academic institution.

5

Authors: Sonia Brugnara, Mariacristina Sicher, Elena Maria Bonandini, Davide Donner, Franca Chierichetti, Mattia Barbareschi, Carlo Renè Girardelli, Orazio Caffo

Here, we report the case of a patient, diagnosed with BRAFV600E-mutated metastatic malignant melanoma M1a, who achieved a complete metabolic response after 7 months of treatment with the combination of dabrafenib and trametinib. After 31 months, the treatment was interrupted for patient’s decision. To date October 2017, 18 months after the interruption of the treatment with the combination of dabrafenib and trametinib, follow-up Positron Emission Tomography (PET) scans are still documenting complete metabolic response.

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Authors: Mariane Teodoro Fernandes MD, Jacob J Adashek BA, Carmelia Maria Noia Barreto MD, Ana Cláudia Barbin Spinosa MD, Barbara de Souza Gutierres MSc, Gilberto Lopes MD, MBA, FAMS, Auro del Giglio MD, PhD, Pedro Nazareth Aguiar Jr MD, MSc

In the last 3 years, a novel class of targeted therapy has been approved for patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer. There are currently three approved agents, which are oral cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. All of the approved drugs exhibit progression-free survival benefit when compared to standard of care and generally have less adverse events compared to traditional chemotherapeutic options. The treatment of HR+/HER2- advanced breast cancer is a continuously evolving landscape, and the addition of CDK4/6 inhibitors is the newest mechanism for treatment. In this review, we summarize all available data, highlight the unanswered questions, and discuss pharmacological differences between each CDK4/6 inhibitor.

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Authors: Sanjay Kalra, Gagan Priya

While lipids are an integral part of the endocrine clinic, the opposite is not necessarily true. The lipocrinology framework addresses this lacuna, by highlighting the similarities and multiple relationships between lipid and endocrine function. It reinforces the need to screen (clinically or biochemically) all dyslipidemic patients for endocrine disease and appropriate endocrine patients for dyslipidemia. Thus, it aims to improve clinical care for persons with lipid abnormalities as well as endocrine disease.

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Authors: Sarah L Anderson PharmD, Joel C Marrs PharmD

Hypertension (HTN) is a common disease state associated with extensive morbidity and mortality worldwide. It is often difficult for patients with HTN to achieve and maintain a goal blood pressure (BP), despite there being many effective treatment options available. Sacubitril/valsartan is a first-inclass angiotensin receptor neprilysin inhibitor (ARNI) that has garnered approval by the US Food and Drug Administration and the European Medicines Agency as a first-line treatment for heart failure with reduced ejection fraction. During clinical trials for heart failure as well as in independent trials for HTN, sacubitril/valsartan has demonstrated safety and efficacy when it comes to BP lowering, making it a promising antihypertensive agent. Most trials of sacubitril/valsartan were 8 to 12 weeks in length and demonstrated a clinically relevant BP lowering that was frequently more significant than its comparators. While more data are needed to confirm its role as an antihypertensive agent, the data available are promising and it is anticipated that sacubitril/valsartan will gain an indication of HTN.

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Authors: Matteo Santoni MD, Francesco Massari MD, Vincenzo Di Nunno MD, Alessandro Conti MD, Alessia Cimadamore MD, Marina Scarpelli MD, Rodolfo Montironi PhD, Liang Cheng PhD, Nicola Battelli MD, Antonio Lopez-Beltran PhD

Advances in understanding the mechanisms of tumour-induced immunosuppression have led to the development of immune-checkpoint inhibitors in cancer patients, including those with renal cell carcinoma (RCC). The optimal combination between immunotherapy and targeted agents (as well as the possible favourable sequential therapy of these two classes of drugs) remains an open question at this moment. Several trials are currently underway to assess the combination of anti-programmed-death 1 (PD-1) or anti-PD-ligand(L)1 agents with other immunotherapies or with anti-vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs). In this editorial, we described the results of the most recent clinical trials on the use of immunotherapies in RCC and the emerging data on the research for reliable biomarkers of tumour response in this setting. In addition, we have focused on the role of the gut microbiome and tumour microenvironment in the development of future therapeutic strategies for RCC patients.

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Authors: Marisa C Liu MD, MPH, Krishnansu S Tewari MD

Over the last decade, new therapeutics in the form of anti-angiogenic treatment, synthetic lethality, and checkpoint inhibition have offered new options for the treatment of ovarian cancer. This review summarizes studies related to these treatment modalities and additionally novel combinations that offer a veritable therapeutic matrix for clinicians to choose from.

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Authors: Marija Vavlukis MD, PhD, FESC, Ana Vavlukis MSc

Background: Statins are the hypolipemic treatment of choice for hyperlipidemia with confirmed atherosclerotic cardiovascular disease (ASCVD) protective effect, proven even in normolipemic patients. But in rare situations, even with a high-dose treatment regimen, or maximally tolerated statin dose treatment, treatment targets of low-density lipoprotein cholesterol (LDL-C), according to the risk profile of the patient, cannot be achieved. Combination therapy with ezetimibe is an effective treatment choice, as it is one of the few hypolipemic drugs with proven ASCVD protective effect. Aim: In this review, we address the question of therapeutic efficacy and safety of ezetimibe in combination therapy with statins, as expressed through its hypolipemic and vasoprotective effects and its potential side effects. Methods: We conducted a literature review of English articles through PubMed, PubMed Central, and Cochrane for randomized clinical trials, retrospective analyses, meta-analyses, and review articles by using key words: ezetimibe, statins, combination therapy, adverse effects. We analyzed data on ezetimibe–statin combination therapy in terms of hypolipemic efficacy, ASCVD risk reduction, and adverse effects. Results: Statins have been proven to be very effective in reducing ASCVD risk, with no apparent threshold at which LDL-C lowering is not associated with reduced risk. Yet, a significant ontreatment residual risk of major cardiovascular (CV) events still exists according to meta-analyses of statin trials. Findings like this point to the unmet needs of the patients on statin treatment. The unmet needs in terms of LDL-C targets and ASCVD risk reduction raise the question of statin combination therapy. Ezetimibe is a cholesterol-lowering drug from the class of cholesterol absorption inhibitors, with the potency to decrease LDL-C by about 10–18% and Apo B by 11–16%, while in combination therapy with statins, an additional LDL-C lowering of 25% or total LDL-C lowering of 34–61% is observed. The effects on LDL-C and other lipoprotein (LP) fractions are translated by ASCVD risk reduction. Ezetimibe is one of the few hypolipemic medications that leads to additional ASCVD risk reduction when added to statin therapy. Present data on ezetimibe support the existence of pleotropic anti-inflammatory and antioxidative effects, in addition to its hypolipemic effect, which are responsible for this added ASCVD risk reduction on top of statin monotherapy. Ezetimibe, in combination therapy with a maximal or maximally tolerated statin therapy, is used in patients who fail to achieve target LDL-C levels with statin monotherapy. In combination with low-to-moderate statin dose treatment, or with second- or thirdline statins, ezetimibe is used in situations of statin-associated muscle symptoms. The combination therapy is relatively safe. Conclusion: Ezetimibe add-on to statin combination therapy is an effective treatment option that leads to additional LDL-C lowering – recommended in situations where, with a maximal or maximally tolerated statin monotherapy treatment regimen, LDL-C targets cannot be achieved. It leads to additional ASCVD risk reduction, without raising significant safety concerns.

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Authors: Constantine E Kosmas MD, PhD, Ian Martinez MD, Andreas Sourlas, Kyriaki V Bouza MD, Frederick N Campos MD, Verenisse Torres MD, Peter D Montan MD, Eliscer Guzman MD

Several prospective epidemiological studies have shown that there is a clear inverse relationship between serum highdensity lipoprotein-cholesterol (HDL-C) concentrations and risk for coronary heart disease (CHD), even at low-density lipoprotein-cholesterol (LDL-C) levels below 70 mg/dL. However, more recent evidence from genetic studies and clinical research has come to challenge the long-standing notion that higher HDL-C levels are always beneficial, while lower HDL-C levels are always detrimental. Thus, it becomes apparent that HDL functionality plays a much more important role in atheroprotection than circulating HDL-C levels. HDL cholesterol efflux capacity (CEC) from macrophages is a key metric of HDL functionality and exhibits a strong inverse association with both carotid intima-media thickness and the likelihood of angiographic coronary artery disease (CAD), independent of the HDL-C level. Thus, extensive research is being conducted to identify new agents with a favorable side effect profile, which would be able to enhance CEC, improve HDL functionality and potentially decrease cardiovascular risk. This review aims to present and discuss the current clinical and scientific evidence pertaining to the significance of HDL functionality over the actual HDL-C concentration in mediating the favorable effects on the cardiovascular system. Thus, we conducted a PubMed search until December 2017 through the English literature using the search terms ‘HDL function/ functionality’, ‘HDL properties’, ‘cardiovascular risk’ and ‘cholesterol efflux capacity’. We also included references from the articles identified and publications available in the authors’ libraries.

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Authors: Pedro Luis Gonzalez MD, MT, Urania Rappo MD, Karthik Akinapelli MS, Jennifer S McGregor RPh, Sailaja Puttagunta MD, Michael W Dunne MD

Background: Persons who inject drugs (PWID) are at increased risk of acute bacterial skin and skin structure infections (ABSSSIs), a growing healthcare concern. Multiple medical, social, and economic issues, including adherence and comorbidities, complicate the medical care of the PWID population, adversely affecting patient outcomes. Methods: We assessed demographics and outcomes for the PWID population in a double-blind trial of 698 patients randomized to dalbavancin 1500 mg as a single intravenous (IV) infusion or as a 2-dose regimen (1000 mg IV on day 1; 500 mg IV on day 8) for ABSSSI. The primary endpoint was ≥20% reduction in erythema at 48–72 hours in the intent-to-treat population; clinical status was also assessed at days 14 and 28. Results: There were 212/698 (30.4%) patients with a history of injection drug use in this clinical trial. Dalbavancin efficacy was similar between the single- and 2-dose therapy groups in the PWID and non-PWID populations at all timepoints. Dalbavancin was well tolerated in the PWID population, with similar rates of adverse events as the non-PWID population. Conclusion: Dalbavancin as a single-dose or 2-dose regimen had similar efficacy for the treatment of ABSSSI at all timepoints in the PWID and non-PWID populations. A single 30-minute IV infusion would eliminate the need for indwelling IV access. The convenience of a single dose supervised in a health setting may also optimize treatment adherence in the PWID population.

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Authors: Nicola Personeni MD, Tiziana Pressiani MD, Armando Santoro MD, Lorenza Rimassa MD

Over the past ten years, sorafenib, a multikinase inhibitor, has been the only systemic agent approved for first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). Whereas only recently lenvatinib was shown to be noninferior to sorafenib, in terms of survival, all other agents previously tested failed to prove noninferiority (or superiority) when compared with sorafenib. Similarly, in a second-line setting, most investigational drugs have failed to provide better survival outcomes than placebo. However, in 2016, data from the RESORCE trial, a phase 3 study evaluating regorafenib in HCC patients who experience disease progression after first-line treatment with sorafenib, have shown a 2.8-month median survival benefit over placebo (10.6 versus 7.8 months). Overall, side-effects were in line with the known safety profile of regorafenib. More recently, the survival benefits of a sustained anti-angiogenic inhibition were demonstrated also with cabozantinib in the frame of the phase 3 CELESTIAL trial. As HCC seems to be an attractive target for immunotherapy, a phase 1/2 trial reported promising efficacy signals from nivolumab, and results of a larger phase 3 trial with another checkpoint inhibitor, namely, pembrolizumab, are still pending. After nearly a decade of a certain degree of stagnation, we are now witnessing a period of novel therapeutic advances with multikinase inhibitors and immunotherapy that will likely change the treatment scenario of HCC.

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Authors: Ariana Papier BA, Lindsay C Strowd MD

Background: Atopic dermatitis is a chronic inflammatory skin condition that affects up to 20% of children and 3% of adults globally. Although topical corticosteroids are considered to be the first-line agents, they can be associated with cutaneous and systemic adverse effects. Since the early 2000s, two new classes of nonsteroid topical therapies, topical calcineurin inhibitors and phosphodiesterase 4 (PDE4) inhibitors, have been introduced and provide a safe treatment alternative. Method: We performed a search and review of clinical trials that examined the safety and efficacy of topical calcineurin inhibitors and PDE4 inhibitors. The search was conducted using the PubMed database as well as preselected keywords and filters. This review focuses on the safety and efficacy of each therapy. Results: Sixty-nine clinical trials identified in this study have demonstrated the efficacy and safety of topical calcineurin and a single novel PDE4 inhibitor in the treatment of atopic dermatitis. Topical calcineurin inhibitors have been shown to be effective in both achieving lesion clearance as well as reducing relapse when used long-term and proactively. Similarly, in clinical trials the PDE4 inhibitor showed success in lesion clearance and symptom management. All three therapies (pimecrolimus, tacrolimus, crisaborole) are associated with low systemic absorption. No clinical trials to date have shown an increased risk of systemic adverse events or malignancy such as lymphoma. The most commonly reported treatment-related adverse event across all three therapies was application-site discomfort, pain or pruritus. It is important to note that longterm studies are not yet available for the novel PDE4 inhibitor. Discussion: Topical calcineurin inhibitors provide a safe and effective alternative to topical corticosteroid use in the treatment of atopic dermatitis. Although the US Food and Drug Administration (FDA) black box warning for topical calcineurin inhibitors remains, studies have not shown an increased risk of malignancy. These warnings have caused a decline in use in favor of topical steroids. A novel PDE4 inhibitor has shown efficacy and safety in studies up to one year. Further long-term safety data is needed.

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Authors: Constantine E Kosmas MD, PhD, Delia Silverio MD, Andreas Sourlas, Frank Garcia MD, Peter D Montan MD, Eliscer Guzman MD

There is extensive evidence demonstrating that there is a clear inverse correlation between plasma high density lipoprotein cholesterol (HDL-C) concentration and cardiovascular disease (CVD). On the other hand, there is also extensive evidence that HDL functionality plays a very important role in atheroprotection. Thus, genetic disorders altering certain enzymes, lipid transfer proteins, or specific receptors crucial for the metabolism and adequate function of HDL, may positively or negatively affect the HDL-C levels and/or HDL functionality and subsequently either provide protection or predispose to atherosclerotic disease. This review aims to describe certain genetic disorders associated with either low or high plasma HDL-C and discuss their clinical features, associated risk for cardiovascular events, and treatment options.

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Authors: Daniel I G Cubero MD, PhD, Beatrice Martinez Zugaib Abdalla MD, Jean Schoueri, Fabio Iazetti Lopes, Karine Corcione Turke, Jose Guzman MD, Auro Del Giglio MD, PhD, Carlos D’Apparecida Santos Machado Filho MD, PhD, Vanessa Salzano MD, Dolores Gonzalez Fabra MD

Background: Currently, molecularly targeted drugs are part of the therapeutic arsenal for the treatment of many neoplasms and are responsible for improvements in the quality of life and survival of patients. Although they act on proteins and components within biochemical pathways that are expressed to a greater extent in neoplastic cells, these drugs can also interfere with the activity of normal cells. Scope: This article reviews the cutaneous side effects of main molecularly targeted cancer therapies for solid tumors. Findings: The use of these drugs causes side effects, and the skin is one of the most commonly affected organs. In this literature review, we discuss the adverse cutaneous effects caused by molecularly targeted drugs. Conclusion: The identification of these reactions is important to both dermatologists and oncologists so that they properly diagnose the reaction and administer adequate treatment, which would allow greater adherence to the oncological treatment and improve patients’ quality of life.

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Authors: Kam Lun Hon MBBS, MD (CUHK), FAAP, FCCM, Kin Fon Leong MBBS, MRCPCH, Theresa Leung MBBS, FRCPCH, FHKAM(Paed), FHKCPaed, Alexander KC Leung MBBS, FRCPC, FRCP(UK & Irel), FRCPCH, FAAP

Background: Eczema or atopic dermatitis (AD) is a common relapsing childhood dermatologic illness. Treatment of AD is primarily topical with emollients and corticosteroid/calcineurin inhibitor, which is efficacious for the majority of patients. However, AD is often complicated and difficult to manage in many Asian cities. Effective therapy is impeded by fallacies in the following aspects: (1) mistrust and unrealistic expectations about Western medicine, (2) skin care and allergy treatment, (3) ambiguity about optimal bathing and moisturizing, (4) hesitation and phobias about the usage of adequate topical corticosteroid and immunomodulatory therapies, (5) food and aeroallergen avoidance and dietary supplementation, and (6) complementary and alternative therapies. Methods and Results: Eleven anonymized case scenarios are described to illustrate issues associated with these fallacies. A literature review is performed and possible solutions to handle or dismiss these fallacies are discussed. Conclusions: The first step in patient care is to accurately assess the patient and the family to evaluate possible concerns, anxiety, and phobias that could impede therapeutic efficacy. Education about the disease should be individualized. Conflicting recommendations on the usage of topical steroid have a detrimental effect on management outcomes, which must be avoided.

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Authors: Alexander KC Leung MBBS, FRCPC, FRCP (UK and Irel), FRCPCH, FAAP, Kam Lun Hon MD, FAAP, FCCM, Theresa NH Leung MBBS, FRCPCH, FHKAM (Paed)

Background: Febrile seizures are the most common neurologic disorder in childhood. Physicians should be familiar with the proper evaluation and management of this common condition. Objective: To provide an update on the current understanding, evaluation, and management of febrile seizures. Methods: A PubMed search was completed in Clinical Queries using the key terms ‘febrile convulsions’ and ‘febrile seizures’. The search strategy included meta-analyses, randomized controlled trials, clinical trials, observational studies, and reviews. Results: Febrile seizures, with a peak incidence between 12 and 18 months of age, likely result from a vulnerability of the developing central nervous system to the effects of fever, in combination with an underlying genetic predisposition and environmental factors. The majority of febrile seizures occur within 24 hours of the onset of the fever. Febrile seizures can be simple or complex. Clinical judgment based on variable presentations must direct the diagnostic studies which are usually not necessary in the majority of cases. A lumbar puncture should be considered in children younger than 12 months of age or with suspected meningitis. Children with complex febrile seizures are at risk of subsequent epilepsy. Approximately 30–40% of children with a febrile seizure will have a recurrence during early childhood. The prognosis is favorable as the condition is usually benign and self-limiting. Intervention to stop the seizure often is unnecessary. Conclusion: Continuous preventative antiepileptic therapy for the prevention of recurrent febrile seizures is not recommended. The use of intermittent anticonvulsant therapy is not routinely indicated. Antipyretics have no role in the prevention of febrile seizures.

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Authors: Alexander KC Leung MBBS, FRCPC, FRCP (UK and Irel), FRCPCH, FAAP, Benjamin Barankin MD, FRCPC, Kin Fon Leong MBBS, MRCPCH, Kam Lun Hon MD, FAAP, FCCM

Background: Penile warts are the most common sexually transmitted disease in males. Clinicians should be familiar with the proper evaluation and management of this common condition. Objective: To provide an update on the current understanding, evaluation, and management of penile warts. Methods: A PubMed search was completed in Clinical Queries using the key terms ‘penile warts’ and ‘genital warts’. The search strategy included meta-analyses, randomized controlled trials, clinical trials, observational studies, and reviews. Results: Penile warts are caused by human papillomavirus (HPV), notably HPV-6 and HPV-11. Penile warts typically present as asymptomatic papules or plaques. Lesions may be filiform, exophytic, papillomatous, verrucous, hyperkeratotic, cerebriform, fungating, or cauliflower-like. Approximately one-third of penile warts regress without treatment and the average duration prior to resolution is approximately 9 months. Active treatment is preferable to watchful observation to speed up clearance of the lesions and to assuage fears of transmission and autoinoculation. Patient-administered therapies include podofilox (0.5%) solution or gel, imiquimod 3.75 or 5% cream, and sinecatechins (polypheron E) 15% ointment. Clinician-administered therapies include podophyllin, cryotherapy, bichloroacetic or trichloroacetic acid, oral cimetidine, surgical excision, electrocautery, and carbon dioxide laser therapy. Patients who do not respond to first-line treatments may respond to other therapies or a combination of treatment modalities. Second-line therapies include topical/intralesional/ intravenous cidofovir, topical 5-fluorouracil, and topical ingenol mebutate. Conclusion: No single treatment has been shown to be consistently superior to other treatment modalities. The choice of the treatment method should depend on the physician’s comfort level with the various treatment options, the patient’s preference and tolerability of treatment, and the number and severity of lesions. The comparative efficacy, ease of administration, adverse effects, cost, and availability of the treatment modality should also be taken into consideration.

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Authors: Montserrat Casamayor MD, PhD, Karen DiDonato MSN, RN, Marc Hennebert MBA, MS, Luca Brazzi MD, PhD, Gregor Prosen MD, FEBEM

Background: Acute pain is among the leading causes of referral to the emergency department (ED) in industrialized countries. Its management mainly depends on intensity. Moderateto- severe pain is treated with intravenous (IV) administered opioids, of which morphine is the most commonly used in the ED. We have estimated the burden of IV administration of morphine in the five key European countries (EU5) using a micro-costing approach. Scope: A structured literature review was conducted to identify clinical guidelines for acute pain management in EU5 and clinical studies conducted in the ED setting. The data identified in this literature review constituted the source for all model input parameters, which were clustered as analgesic (morphine), material used for IV morphine administration, nurse workforce time and management of morphine-related adverse events and IV-related complications. Findings: The cost per patient of IV morphine administration in the ED ranges between €18.31 in Spain and €28.38 in Germany. If costs associated with the management of morphine-related adverse events and IV-related complications are also considered, the total costs amount to €121.13–€132.43. The main driver of those total costs is the management of IV-related complications (phlebitis, extravasation and IV prescription errors; 73% of all costs) followed by workforce time (14%). Conclusions: IV morphine provides effective pain relief in the ED, but the costs associated with the IV administration inflict an economic burden on the respective national health services in EU5. An equally rapid-onset and efficacious analgesic that does not require IV administration could reduce this burden.

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Authors: Youngjung Kim, Laura Hack, Elizabeth S Ahn, Jungjin Kim

Alcohol use disorder (AUD) is commonly encountered in clinical practice. A combination of psychosocial intervention and pharmacotherapy is the cornerstone of AUD treatment. Despite their efficacy, safety and cost-effectiveness, clinicians are reluctant to prescribe medications to treat individuals with AUD. Given the high rate of relapse with psychosocial intervention alone, increasing patient access to this underutilized treatment has the potential to improve clinical outcome in this difficult-to-treat population. Herein, we provide practical pharmacotherapy strategies to improve treatment outcome for AUD. We review the efficacy and side effects of both on- and off-label agents with a particular focus on clinical applicability. Recommendations are supported by findings from randomized controlled trials (RCT) and meta-analyses selected to be representative, where possible, of current treatment guidelines. The goal of this paper is to help readers use pharmacotherapy with greater confidence when treating patients with AUD.

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Authors: Milena M McLaughlin PharmD, MSc, Aimee J Guerrero BS, Andrew Merker PharmD

A review of literature published regarding non-tenofovir antiretroviral agents causing renal adverse effects was conducted. The literature involving renal adverse effects and antiretroviral therapy is most robust with protease inhibitors, specifically atazanavir and indinavir, and includes reports of crystalluria, leukocyturia, nephritis, nephrolithiasis, nephropathy and urolithiasis. Several case reports describe potential nephropathy (including Fanconi syndrome) secondary to administration of abacavir, didanosine, lamivudine and stavudine. Case reports documented renal events such as acute renal failure, nephritis, proteinuria and renal stones with efavirenz administration. Regarding rilpivirine, a small increase of serum creatinine levels (SCr) was found in clinical trials; however, the clinical significance and impact on actual renal function is unknown. The integrase strand transfer inhibitors and enfuvirtide have a relatively safe renal profile, although studies have shown dolutegravir and raltegravir cause mild elevations in SCr without an impact on actual renal function. This is similar to the reaction observed with cobicistat, the pharmacokinetic enhancer frequently given with elvitegravir.

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Authors: Margarita SaizSatjes, Francisco Javier Martinez-Martin

Antihypertensive treatment of patients with diabetes should include those drugs with a positive effect on metabolic parameters. Most patients with diabetes require at least two antihypertensive agents. Combining a dihydropyridine calcium channel blocker with a renin-angiotensin-aldosterone system inhibitor is a rational approach. However, not all dihydropyridines are equal with respect to their effects on metabolic parameters. Thus, manidipine exerts a positive effect on insulin resistance. However, this effect has not been observed with amlodipine. On the other hand, the excessive activation of sympathetic nervous system has been related with an increase of insulin resistance, pulse pressure, and ankle edema rates. Compared with amlodipine, manidipine activates sympathetic nervous system to a lesser extent. As a result, treatment with manidipine represents a good option in hypertensive patients with diabetes.

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Authors: Carlos Blanco MD, PhD, Raphaelle Bazire MD, Laura Argiz MD, Jenaro Hernández-Peña MD, PhD

The objective of the systematic review is to provide complete and updated information on efficacy and safety of sublingual immunotherapy (SLIT) formulations for the treatment of allergic respiratory diseases (ARDs). The literature search was conducted on PubMed database, involving double-blind, randomized clinical trials published between January 1992 and 2018, written in English, and performed in humans. The number of articles finally selected for review was 112. Data from the majority of properly controlled clinical trials demonstrate that SLIT is effective not only with short-term use (first year) but also with long-term use (up to the third year of active therapy), for treating ARDs in children and adults. Both continuous and discontinuous schemes of administration showed significant reductions in symptom and medication scores. Moreover, a SLITinduced disease-modifying effect has been documented mainly with grass pollen extracts, since improvement is maintained during at least 2 years of follow-up after a 3-year treatment period. Additionally, allergen immunotherapy should also be considered a preventive strategy, especially for decreasing bronchial asthma incidence in children and adolescents with allergic rhinitis treated with SLIT. This therapy is also safe, producing only a few mainly local and mild-to-moderate adverse events, and usually self-limited in time. The registration and authorization of allergen SLIT preparations (grasses and house-dust mite tablets) as drugs by regulatory agencies, such as the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA), has represented a landmark in allergy immunotherapy research. Further long-term studies, specially designed with allergens other than grass pollen or house-dust mites, not only in allergic rhinoconjunctivitis but also on asthmatic subjects, as well as studies comparing different administration schedules and/or routes, are required in order to continue the progress in the modern development of this particularly promising therapy.

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Authors: Elizabeth S Nakasone MD, PhD, Sara A Hurvitz MD, Kelly E McCann MD, PhD

Breast cancer is the most prevalent malignancy in women and the second most common cause of cancer-related death worldwide. Despite major innovations in early detection and advanced therapeutics, up to 30% of women with nodenegative breast cancer and 70% of women with node-positive breast cancer will develop recurrence. The recognition that breast tumors are infiltrated by a complex array of immune cells that influence their development, progression, and metastasis, as well as their responsiveness to systemic therapies has sparked major interest in the development of immunotherapies. In fact, not only the native host immune system can be altered to promote potent antitumor response, but also its components can be manipulated to generate effective therapeutic strategies. We present here a review of the major approaches to immunotherapy in breast cancers, both successes and failures, as well as new therapies on the horizon.